During the 2021 Society for Immunotherapy of Cancer (SITC) Annual Meeting, being held virtually and in person in Washington, D.C. from Nov. 10-14, 2021, Bolt Biotherapeutics presented updated data from three of its pipeline programs, including BDC-2034, a PD-L1 Boltbody ISAC and the company’s Myeloid Modulator Platform. Each of the presentation highlighted the progress made in preclinical studies to demonstrated the potential for each pipeline candidate as a novel approach for the treatment for cancer.

“We are presenting new data for three of our pipeline programs that demonstrate the depth of our technology platform and the expertise of our team in modulating myeloid cell biology to develop promising therapeutic candidates,” noted David Dornan, Ph.D., Bolt Biotherapeutics’ Chief Scientific Officer.

“Repolarizing tumor-associated macrophages, or TAMs, to become tumor destructive via the novel target Dectin-2 (also known as TAM1) is groundbreaking work that may be synergistic with our entire Boltbody ISAC portfolio. Our work targeting CEA and PD-L1 reinforces our commitment to develop therapeutics that could have promising activity against solid tumors where limited treatment options are available,” Dornan added.

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Precision targeting
Immune-Stimulating Antibody Conjugates or ISACs are a new category of immunotherapy that combines the precision of antibody targeting with the strength of the innate and adaptive immune systems.

Boltbody ISACs comprise three primary components: a tumor-targeting antibody, a non-cleavable linker, and a proprietary immune stimulant to activate the patient’s innate immune system.

By initially targeting a single marker on the surface of a patient’s tumor cells, an ISAC can create a new immune response by activating and recruiting myeloid cells. The activated myeloid cells start a feed-forward loop by releasing cytokines and chemokines, chemical signals that attract other immune cells and lower the activation threshold for an immune response. This reprograms the tumor microenvironment and invokes an adaptive immune response that targets the tumor, with the goal of durable responses for patients with cancer.

Applying Boltbody™ platform technology, scientists at Bolt have developed a novel carcinoembryonic antigen (CEA-) targeting ISAC called BDC-2034. The investigational agent is designed to exploit over-expression of CEA in cancers and trigger the innate immune system, leading to adaptive anti-tumor immunity and tumor destruction.

BDC-2034 comprises a novel antibody with selective binding to CEACAM5 that displays high levels of antibody-dependent cellular phagocytosis of CEA-expressing cancer cells. The CEA-targeted, pro-phagocytic antibody is conjugated to a proprietary TLR7/8 agonist payload. Both elements of this molecule are finetuned for selective immune activation in tumors.

In preclinical studies, researchers observed robust myeloid cell activation in vitro and promising anti-tumor activity in vivo.

New data reported at SITC 2021 demonstrate both tumor cell clearance and innate immune activation in cellular and in vivo models of CEA-expressing cancers. Further, systemic administration in tumor-bearing animals results in tumor-selective immunity. Based on these data, Bolt Biotherapeutics designated BDC-2034 as a clinical candidate and is currently conducting IND-enabling studies with the expectation to initiate BDC-2034 clinical development in 2022.

BDC-2034 is in development for the treatment of various solid tumors.

From “Cold” to “Hot”
Carcinoembryonic antigen or CEA is a well-known tumor antigen that is overexpressed in various solid tumors with significant unmet medical need including, but not limited to, colorectal cancer, non-small cell lung cancer, pancreatic cancer and breast cancer. CEA is upregulated on the cell surface of these cancers and displays minimal receptor-mediated internalization into the cancer cell. Therefore, CEA allows allows the targeting of these cancers, some of which are immunologically “cold,” with an ISAC and offers the potential to turn these “cold” tumors into “hot” tumors with a robust immunological response.

During the annual meeting, Bolt’s scientists, for the for the first time presented preclinical data on a novel multifunctional PD-L1-targeted Boltbody ISAC that has demonstrated the potential to improve upon the efficacy of PD-L1/PD-1 inhibition, especially in tumor types that do not respond well to immune-checkpoint inhibition. Bolt Biotherapeutics’ PD-L1 ISAC uniquely combines three mechanisms of action including the ADCP and myeloid cell activation of an ISAC, plus immune-checkpoint inhibition with the ability to act through PD-L1 expressed on both tumor and immune cells.

The presented data also demonstrated how PD-L1 ISAC induces robust, target-dependent
activation of the immune system, including induction of immunological memory. Overall, the based on the outcome of the preclinical studies, researchers found that treatment with PD-L1 ISACs led to an effective anti-tumor response that was substantially improved over PD-L1 antibody blockage in preclinical models.

Tumor macrophage reprogramming
Dectin-2, formerly referred to as TAM1, as a novel target for cancer immunotherapy. Expressed by tumor-associated macrophages (TAMs), Dectin-2 is a pattern recognition receptor that stimulates proinflammatory cytokine production and antigen presentation to drive innate and adaptive immune responses. The findings  reported at SITC 2021 demonstrate that agonism of Dectin-2 on TAMs elicits secretion of pro-inflammatory cytokines and chemokines capable of invoking productive anti-tumor immunity.  Researchers found that in murine tumor models, Dectin-2 agonism mediates anti-tumor efficacy in a CD8 T-cell dependent manner and induces immunological memory against the tumor.

Scientists at Bolt Biotherapeutics have generated Dectin-2 agonist antibodies that demonstrate the potential to reprogram tumor-supportive macrophages into tumor-destructive macrophages.

[1] BDC-2034: Discovery of a CEA-targeting Immune-Stimulating Antibody Conjugate (ISAC) for Solid Tumors. Poster #784, Presented by: William G. Mallet, Ph.D. on Saturday, Nov. 13, 2021, 7:00 a.m. – 8:30 p.m. EST, Poster Hal
[2] PD-L1-targeted ISAC combines myeloid cell activation, immune-checkpoint inhibition and ADCP to improve anti-tumor efficacy over anti-PD-L1 antibodies in preclinical models. Poster #782, Presented by: Marcin Kowanetz, Ph.D. on Saturday, Nov. 13, 2021, 7:00 a.m. – 8:30 p.m. EST, Poster Hal
[3] Dectin-2, a novel target for tumor macrophage reprogramming in cancer immunotherapy. Poster #862, Presented by Justin A. Kenkel, Ph.D. on Saturday, Nov. 13, 2021, 7:00 a.m. – 8:30 p.m. EST, Poster Hal

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